This application for supplementary funding to the Baylor College of Medicine Mental Retardation and Developmental Disabilities Research Center seeks to renew a collaborative Fragile X Syndrome Research Center composed of investigators at Baylor College of Medicine in Houston, TX and Emory University School of Medicine in Atlanta, GA. The application seeks continued support for three investigator-initiated research projects, plus funding for a fourth project and for three core facilities. The four projects will revolve around a common theme of determining the full spectrum of phenotypes and their underlying pathological causes in humans and mice with genetic alterations in the FMR1 gene, with a goal of discovering and testing effective treatment. An Administrative Core will be proposed to facilitate interactions among the four investigative groups and the two institutions, and funding is sought to expand core services currently provided by the BCM MRDDRC Mouse Neurobehavior Core directed by Dr. Richard Paylor. Additional support will allow the core to expand services into the area of measurement of the efficacy of treatment. The four investigators proposing projects are Drs. David Nelson and Richard Paylor of Baylor College of Medicine, and Drs. Stephen Warren and Stephanie Sherman of Emory University. Each of these investigators has a strong track record of research into fragile X syndrome, and there have been extensive collaborative interactions among these investigators spanning two decades. Dr. Nelson's project is the new addition to the Center, with a focus on using mouse models to understand the developmental timing requirements for FMR1. Dr. Sherman will continue her studies of the human male premutation phenotype that involves late onset tremor and cognitive decline. Dr. Warren will test drug treatments in fly models and mouse neurons, and Dr. Paylor will focus on measuring behavioral and electrophysiological responses to genetic alterations to the Fmr1 knock-out mouse model. Dr. Gary Bassell will establish a Neuronal Imaging Core at Emory University. Dr. Bassell also has a strong track record in research into fragile X syndrome, and is an expert in imaging molecules in neurons. He proposes a core that will offer his expertise to the projects proposed in the Center, allowing better definition of phenotypes in mouse models and methods to assess treatment outcomes. These projects offer improved understanding of the function of FMR1 and potential treatments. [unreadable] [unreadable] [unreadable]